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Renin-angiotensin Aldosterone system
The renin-angiotensin aldosterone system (RAAS) is a hormonal cascade regulated by the perfusion pressure in the kidneys. The classical model sets up a negative feedback cycle in which the active product, Ang II inhibits product of renin hence creating a homeostatic system. RAAS is also responsible for controlling fluid balance, hypertension, and cardiovascular activity. The RAAS system is closely linked to the sympathetic nervous system, and drugs that target it interact with each other and with beta-blockers. History The first evidence for renin was produced over 100 years ago (Jensen 2008) but the full RAAS pathway was not understood as a target for theraputic drugs until the 1970s. angiotensin was also known as hypertensin in the US and angiotonin, angiotensin is a compromise. There is a "classical" RAAS, and then a series of speculative pathways with less well understood biological effects, these alternative pathways are referred to as "escape" pathways as they allow sidestepping of the drug activities of the ACEI and ARBs Further Ang molecules through to Ang 1-9 have been identified, which have yet to be thoroughly studied. The first drugs targetted at the RAAS system were ACE inhibitors, which competed with ACE to reduce the level of Ang I to Ang II conversion. In the 1990s the Ang II receptor blockers (ARBs) were developed that interfered with the final step of the cascade. Both ACEI and ARB type drugs result in feedback interference and result in higher levels of plasman renin activity (PRA) (Jensen 2008) Aliskiren (an inhibitor of renin production) was approved for the treatment of hypertension in 2007 (Jensen 2008) Aliskiren is considered a 3rd generation direct renin inhibitor. Biological Pathway Angiotensinogen is a large glomular protein produced in the liver and released as a result of constituitive secretion. The level of angiotensinogen is relatively stable in the blood. #Pathway is initiated by the secretion of renin #Renin regulates the initial step by cleaving the N-terminal portion of angiotensionogen to form Ang I #ACE hydrolyses the C-terminal dipeptide of Ang I to form Ang II #Ang II activation of the AT_1 receptor stimulates the production of Aldosterone The RAAS system is a cascade of proteolytic cleavages initiated by the secretion of the enzyme renin by the kidney, and leading to the production of angiotensin II. Dysregulation of RAAS leads to cardiac disorders Currently 3 proteins in the RAAS pathway are targetted with drugs; #Renin #Angiotensin Converting Enzyme #Ang II It is claimed that the effect of ACE inhibitors on BP decreases over time due to the existence of Ang I to Ang II conversion which is not catalyzed by the ACE protein. Renin The renin-angiotensin aldosterone hormonal cascade begins with the biosynthesis of renin by the juxtaglomerular cells (JG) that line the afferent (and occasionally efferent) arteriole of the renal glomerulus. Renin is synthesized as a preprohormone, and mature (active) renin is formed by proteolytic removal of a 43-amino-acid prosegment peptide from the N-terminus of pro- renin, the proenzyme or renin precursor. Mature renin is stored in granules of the JG cells and is released by an exocytic process involving stimulus-secretion coupling into the renal and then the systemic circulation. In addition to this regulated pathway, it appears that the kidney also releases unprocessed prorenin via a constitutive pathway. In fact, prorenin accounts for about 70% to 90% of the immunoreactive renin in the human circulation. The potential biological significance of this finding is poorly understood at present. Atlas, S. A. (2007) ‘The renin–angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition’, J. Manag. Care Pharm., 13, (8 Suppl. B), pp. 9–20. How is renin secretion regulated #renal baroreceptor afferent #"changes in delivery of NaCl to macula densa cells of distal tubule" JG Apparatus #Sympathetic nerve stimulation via beta-1 adrenergic receptors #negative feedback by a direct action of Ang II on the JG cells (renin is synthesised in other tissues, but the factors and actions are poorly understood) Angiotensinogen Is produced in the liver and released by constituitive secretion, hence blood levels are stable. "constitutive secretion. Proteins are continuously secreted from the cell regardless of environmental factors. No external signals are needed to initiate this process. Proteins are packaged in vesicles in the Golgi apparatus and are secreted via exocytosis, all around the cell." Angiotensinogen is a plasma-substrate released by the liver Angiotensin Converting Enzyme (ACE) "ACE is a membrane bound exopeptidase and is localized on the plasma membrances of various types of cell" ACE is also known as kinase II, metabolizes a number of other peptides bradykinin, and kalliin is nearly ubiquitous on vascular endothe-lium Ang I is a biologically inert decapeptide is hydrolysed by ACE to II Ang II Hormone that effects blood pressue, acts as a potent vasoconstrictor ACE removed the C-terminal dipeptide to form the ocatapeptide Ang II Subsequent data showed a role for angiotensin II in long-term effects on cardiovascular structure, including cardiac hypertrophy and vascular remodeling. “Angiotensin II and the Endothelium: Diverse Signals and Effects.” Journal of the American Heart Association (n.d.). http://learn2.open.ac.uk/pluginfile.php/389147/mod_resource/content/1/Watanabe_xyz1.pdf. cardiac hypertrophyvascular remodellingrenal fibrosis Aldosterone Produced and released from the adrenal cortex. regulates sodium and potassium balance Aldoesterone is a hormone which causes increasesd blood pressure, and sodium reabsorption Production stimulated by Ang II at the AT_1 receptor "Also stimulates the production of aldosterone by the zona glomerulosa, the outermost zone of the adrenal cortex" (Atlas) Aldosterone is a major regulator of sodium and potassium balance and thus plays a major role in regulating extracellular volume. Angiotensin Receptor subtypes At least 4 Angiotensin receptors subtypes have been discovered (Atlas) AT_1R is widely distributed AT_2R is highly expressed only in the fetus, but in adults low levels of AT_2R expression occur in aorta and coronary artieries. (Batenburg WW, Garrelds IM, Bernasconi CC, Juillerat-Jeanneret L, Van Kats JP, Saxena PR, Danser AH. Angiotensin II Type 2 Receptor-Mediated Vasodilation in Human Coronary Microarteries. Circulation. 2004. In addition, the beneficial effects of ARBs on cardioprotection are mediated in part by an AT2R-dependent pathway. “Angiotensin II and the Endothelium: Diverse Signals and Effects.” Journal of the American Heart Association (n.d.). http://learn2.open.ac.uk/pluginfile.php/389147/mod_resource/content/1/Watanabe_xyz1.pdf.AT_4R Exciting new data from Feng et al35 showed that the AT2R coupled to the G protein ␣s (G␣s) independent of G␤ and G␥. Main drug strategies #Angiotensin converting enzyme (ACE) inhibitors #Angiotensin receptor antagonists #renin inhibitors Angiotensin is formed in extracellular space renin - rate limiting enzyme that catalyzes the hydrolysis of angiotensin (Ang) 1 from the N-terminus of angiotensinogen Ang II is a potent vasoconstrictor Ang II is the active product of RAAS Other metabolites of RAAS might have biological impact Drugs that interfere with the secretion or action of aldosterone are in use as antihypertensives. Angiotensin II is a potent vaso-active peptide that causes blood vessels to constrict, resulting in increased blood pressure. In general, there are two different patterns of secretion. One pattern is called constitutive secretion. Proteins are continuously secreted from the cell regardless of environmental factors. No external signals are needed to initiate this process. Proteins are packaged in vesicles in the Golgi apparatus and are secreted via exocytosis, all around the cell. Cells that secrete constitutively have Golgi apparatus scattered throughout the cytoplasm. Fibroblasts, osteoblasts and chondrocytes are some of the many cells that perform constitutive secretion. Enzymes such as cathepsin G and elastase are thought to directly convert angiotensinogen to angiotensin II, and chymases and cathepsin G are thought to provide an alternative pathway for the conversion of angiotensin I to angiotensin II